Cerebral microbleeds and vascular cognitive impairment

https://doi.org/10.1016/j.jns.2010.08.034Get rights and content

Abstract

MRI manifestations of small vessel diseases including white matter hyperintensities and lacunes have been recognized as potential substrates of vascular cognitive impairment for many years. Cerebral microbleeds (CMBs) ā€“ small, perviascular haemorrhages seen as small, well-demarcated, hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility effects ā€“ are also now recognized as an imaging marker for small vessel pathology, but their clinical impact on cognition remains uncertain. CMBs are present in about a third of patients with ischaemic stroke, and in a high proportion of patients with Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. They have also been increasingly found in normal elderly populations, particularly using sequences optimized for their detection. Some recent studies have suggested an effect of CMBs on cognition, which could relate directly to focal damage to or dysfunction of adjacent brain tissues; alternatively, CMBs may be a more general marker for the severity of small vessel pathology related to hypertension or cerebral amyloid angiopathy. CMBs may therefore play a role in understanding the underlying mechanisms of vascular cognitive impairment, in diagnosis, and in assessing its severity and prognosis; this review considers recent evidence on this topic.

Introduction

Vascular cognitive impairment (VCI) is a key healthcare challenge facing all aging Western societies, second only to Alzheimer's Disease (AD) as a cause of dementia [1]. Initial concepts of VCI invoked cortical or subcortical infarction ā€“ leading to the terms ā€œmulti-infarct dementiaā€ and ā€œpost-stroke dementiaā€. However subcortical small vessel disease (often not causing acute or overt clinical symptoms) also plays a critical role in VCI [2], [3], [4]. MRI is the most important tool for detecting and quantifying small vessel diseases, and forms part of current diagnostic criteria for vascular dementia [1]. MRI manifestations of small vessel diseases including white matter hyperintensities (WMH: bright signal areas on T2-weighted or FLAIR images including leukoaraiosis) and lacunes have been recognized for many years. Cerebral microbleeds (CMBs) ā€“ small, perviascular haemorrhages seen as well-demarcated, rounded lesions on MRI sequences sensitive to magnetic susceptibility ā€“ are also now recognized as a manifestation of small vessel pathology [5] (Fig.Ā 1), but their clinical impact on cognition remains uncertain [6]. This review will consider how CMBs may be relevant in the study of VCI.

White matter lesions (WML), also termed white matter changes, white matter hyperintensities, or leukoaraiosis, appear on T2-weighted MRI sequences as regions of high signal in the periventricular or subcortical white matter. WML appear on CT as areas of relative hypoattenuation in the same regions. The pathological correlates of WML include myelin loss, gliosis, axonal loss, microinfarction and dilation of perivascular spaces. [7] The precise pathogenesis of WML is unknown, but there is substantial evidence that they are related to vascular disease; one hypothesis is that WML are related to chronic hypoperfusion in the territory of small perforating arteries, a proposal supported by neuroimaging evidence of hypoperfusion within white matter regions [8], [9]. Epidemiologic studies show strong relationships between WML and vascular risk factors, ischemic stroke and intracerebral hemorrhage. Furthermore it is clear that small vessel arterial disease can itself cause WML, as patients with the hereditary vascular diseases CADASIL and familial CAA present with extensive WML at a relatively early age, when conventional risk factors and ageing are unlikely to make a major contribution. Correlations of WMH with cognition have often been modest, particularly in patients with symptomatic cerebrovascular disease [10], [11]. The limited correlations in some studies may be a reflection of both the pathological heterogeneity of small vessel diseases, and the lack of pathological specificity of conventional MRI, whose signal is largely related to the local concentration of water protons. Tissue water content may be affected by many pathological processes including infarction, ischaemic demyelination and gliosis, which may have different functional effects. There is thus a need for a better understanding of the pathological basis of MRI changes, and for more specific imaging markers to detect and quantify small vessel pathology.

Another reason that previous correlations of MRI changes and cognition have been limited is that VCI and AD have generally been considered as separate, non-overlapping entities. This dichotomy is an oversimplification, since both VCI and AD are diseases of older people and commonly co-exist. Furthermore, vascular and degenerative processes have complex interactions and, potentially, synergistic deleterious effects on brain function. For example, hypertension is a risk factor for developing AD, and WMH are commonly found on the MRI scans of people with AD [12]. It has also been hypothesized that pre-existing AD pathology may make people with stroke more vulnerable to post-stroke cognitive decline [13]. However, exactly how these pathologies are linked remains a critical question in understanding mechanisms of dementia. A key question is whether AD and cerebrovascular disease simply co-exist in some individuals, or do these pathological processes interact? One intriguing process that may link cerebrovascular disease with AD is cerebral amyloid angiopathy (CAA). CAA is characterized by amyloid deposition (principally in cortical and leptomeningeal small vessels), and is common with advancing age and in AD, as well as being an important cause of spontaneous intracerebral haemorrhage in older individuals [14]. One possibility is that vascular amyloid adversely affects vessel reactivity and small vessel function, causing ischaemic damage (white matter ischaemia or frank cortical/subcortical small infarcts). Alternatively, ischaemic damage to small arteries and veins could lead to impaired clearance of amyloid and its deposition in vessel walls [15]. There is clearly a need to explore how hypertensive small vessel disease, amyloid angiopathy and AD interact to cause cognitive impairments. CMBs may be particularly interesting in this regard, because they appear to be related to both CAA (in patients with or without AD) and hypertensive small vessel damage.

CMBs are radiological lesions due to small collections of old blood products (in particular, haemosiderin contained within perivascular macrophages) that have previously leaked from cerebral vessels affected by small vessel pathologies ā€“ mainly lipohyaline degeneration (related to hypertension) or amyloid angiopathy [5]. CMBs appear as small, well-demarcated, hypointense, rounded lesions up to about 5ā€“10Ā mm in diameter on MRI sequences sensitive to their paramagnetic magnetic susceptibility effect ā€“ most commonly gradient-echo T2* sequences. The available evidence suggests that radiologically-defined CMBs are quite specific for perivascular haemosiderin deposits adjacent to small-calibre vessels [5], [16], providing careful attention is paid to avoiding the misclassification of CMB ā€œmimicsā€ including pial sulcal blood vessels, mineralization (e.g. basal ganglia calcification), or susceptibility effects at air-bone interfaces [5], [17]. Some CMBs have been associated with microaneurysmal or pseudoaneurysmal lesions [18], [19], [20]. CMBs are commonly found in patients with cerebrovascular diseases, including first-ever or recurrent ischaemic or haemorrhagic stroke [21], [22], and in AD and vascular dementia (VaD) defined according to standard criteria [23], [24]. The distribution of CMBs may reflect the underlying type of small vessel disease: it is hypothesized (but not proven) that CMBs in an exclusively deep distribution result from hypertensive arteriopathy, whilst those at the cortico-subcortical boundaries of the cerebral lobes are related to CAA [25]. Thus, CMBs may have promise to detect, quantify and map the effects of small vessel disease and amyloid deposition in patients with cognitive impairment. They may be more specific for the underlying pathology than some other imaging manifestations of small vessel diseases (e.g. WMH), particularly if their anatomical distribution can be mapped [17]. The mechanism(s) by which CMBs might influence cognitive function remain speculative, but could include direct structural damage to surrounding tissue [26], functional disturbances in surrounding tissue, or because of disturbed small vessel reactivity and function.

Section snippets

Studies of cerebral microbleeds and cognition

Please see Table 1 for a summary of studies of the impact of CMBs on cognition in different populations, which are discussed in more detail below.

Future research directions

Much of the previous imaging research has concentrated on one or two MRI manifestations of cerebrovascular disease in isolation, e.g. WMH or lacunes. However, future research should aim to investigate all available imaging markers of cerebrovascular disease together, perhaps in broad clinical cohorts with a range of VCI pathologies (large vessel territorial infarcts, subcortical ischaemic vascular disease, etc.). White matter changes, lacunes, CMBs, as well as cortical infarcts could all be

Conclusions

CMBs are now accepted as a manifestation of cerebral small vessel pathologies, including hypertensive small vessel disease and CAA. CMBs are increasingly detected in normal elderly populations, and in all types of cerebrovascular disease; they are highly prevalent in both VCI and AD. Some studies in VCI, AD and normal individuals have shown a relationship between CMBs and cognition. However, the impact of CMBs on cognitive function in different patient populations remains unclear, and the

Role of funding

David Werring is supported by a Department of Health and Higher Educational and Funding Council for England Clinical Senior Lectureship Award. Simone Gregoire was supported by a grant from The Stroke Association. This work was undertaken at UCLH/UCL who received a proportion of funding from the UK Department of Health's National Institute for Health Research Biomedical Research Centers funding scheme (UCLH/UCL Comprehensive Biomedical Research Trust). The funding sources had no role in any

Conflict of interest

None.

References (34)

  • S.M. Greenberg et al.

    Cerebral microbleeds: a guide to detection and interpretation

    Lancet Neurol

    (2009 Feb)
  • M.G. Hennerici

    What are the mechanisms for post-stroke dementia?

    Lancet Neurol

    (2009 Nov)
  • S.T. Pendlebury et al.

    Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis

    Lancet Neurol

    (2009 Nov)
  • V. Hachinski et al.

    National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards

    Stroke

    (2006 Sep)
  • E.J. van Dijk et al.

    Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study

    Stroke

    (2008 Oct)
  • S. Black et al.

    Vascular cognitive impairment: small vessels, big toll: introduction

    Stroke

    (2009 Mar)
  • J.V. Bowler

    Modern concept of vascular cognitive impairment

    Br Med Bull

    (2007)
  • H.C. Koennecke

    Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications

    Neurology

    (2006 Jan 24)
  • F. Udaka et al.

    White matter lesions and dementia: MRI-pathological correlation

    Ann NY Acad Sci

    (2002 Nov)
  • M. O'Sullivan et al.

    Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis

    Neurology

    (2002 Aug 13)
  • H.S. Markus et al.

    Reduced cerebral blood flow in white matter in ischaemic leukoaraiosis demonstrated using quantitative exogenous contrast based perfusion MRI

    J Neurol Neurosurg Psychiatry

    (2000 Jul)
  • J.C. van Swieten et al.

    Are white matter lesions directly associated with cognitive impairment in patients with lacunar infarcts?

    J Neurol

    (1996 Feb)
  • O. Sabri et al.

    Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy

    Stroke

    (1999 Mar)
  • R. Barber et al.

    White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dementia, and normal aging

    J Neurol Neurosurg Psychiatry

    (1999 Jul)
  • H.V. Vinters

    Cerebral amyloid angiopathy. A critical review

    Stroke

    (1987 Mar)
  • C. Iadecola et al.

    Threats to the mind: aging, amyloid, and hypertension

    Stroke

    (2009 Mar)
  • F. Fazekas et al.

    Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds

    AJNR Am J Neuroradiol

    (1999 Apr)
  • Cited by (117)

    • Structural changes in the aging brain

      2020, Handbook of Mental Health and Aging
    View all citing articles on Scopus
    View full text